MONITORING INTERNATIONAL TRENDS

posted January 2013

The NBA monitors international developments that may influence the management of blood and blood products in Australia. Our focus is on:

  • Potential new product developments and applications; and
  • Global regulatory and blood practice trends; and
  • Events that may have an impact on global supply, demand and pricing, such as changes in company structure, capacity, organisation and ownership; and
  • Other emerging risks that could potentially put financial or other pressures on the Australian sector.

A selection of recent matters of interest appears below:

Products

Here the NBA follows the progress in research and clinical trials that may within a reasonable timeframe make new products available, or may lead to new uses or changes in use for existing products.

a)The 54th Annual Meeting and Exposition of the American Society of Hematology (ASH) was held in Atlanta, Georgia in December 2012. Amongst the presentations:

  1. Baxter International announced Phase I/III study results evaluating the safety and efficacy of BAX 326, an investigational recombinant factor IX (rFIX) protein, for the treatment and prophylaxis of bleeding episodes for patients with hemophilia B over 12 years of age. BAX 326 was recently granted orphan-drug designation by the U.S. Food and Drug Administration (FDA), a special status given to a product that when approved, will address an unmet need for people with a rare disease or condition. Data supporting the prophylaxis indication, which is the basis for the orphan drug designation, was included in the biologics license application (BLA). The Phase I/III prospective, controlled, multicentre study investigated the pharmacokinetics, efficacy and safety of BAX 326 in 73 previously-treated patients with severe or moderately severe hemophilia B. Results from the study showed that twice-weekly prophylactic treatment with BAX 326 achieved a median annualized bleed rate of 1.99 with 43 percent of patients experiencing no bleeds[1].
  2. Inspiration Biopharmaceuticals announced interim clinical results for two products- its intravenous recombinant porcine factor VIII (OBI-1) for treating serious bleeds in acquired hemophilia A[2]; andrFIX(IB1001) for treating and preventing bleeding in haemophilia B in children under 12[3].
  3. Inspiration will file a BLA for OBI-1 in the first half of 2013. OBI-1 has orphan drug designation in the US and EU, has fast track designation from the FDA. This designation is for a drug intended to treat a serious disease and which has a potential to fill an unmet medical need. It may receive priority review (eight months).
  4. Inspiration filed a marketing authorization application in Europe for IB1001 late in 2011 and a BLA license application in the US for IB1001 in the first half of 2012. Regulatory reviews are ongoing[4].
  5. Ipsen and Inspiration made some changes in their partnership arrangements in 2012. In January 2013, Baxter announced it will be acquiring OBI-1 and related assets.
  6. Alnylam Pharmaceuticals presented new pre-clinical data from its RNAi therapeutic program for the treatment of haemophilia and other bleeding disorders. Data showed that ALN-AT3, a subcutaneous RNAi therapeutic targeting antithrombin (AT), delivers “potent, dose-dependent, and durable knockdown of AT in non-human primates with an up to four-fold increase in thrombin generation”. The company said the drug is expected to be subject to an investigational new drug filing in mid-2013.
  7. AesRx announced data from its Phase I study for its drug Aes-103 shows the treatment is safe and well-tolerated for patients with sickle cell disease. The drug has orphan drug status from the FDA.
  8. Emmaus Medical discussed its sickle cell research. It had earlier announced the completion of patient enrolment for its Phase III trial to study L-glutamine as a treatment for sickle cell anemia and beta-thalassemia. L-glutamine therapy for these conditions is a patent protected treatment, which has orphan drug status in both he US and Europe. It has fast track designation from the FDA.
  9. Acetylon Pharmaceuticals announced results from a preclinical study of a selective histone deacetylase (HDAC) 1/2 inhibitor for the treatment of sickle cell disease and beta-thalassemia. The study results suggest that selective inhibition of the epigenetic regulators of gene expression, HDACs 1 and 2, could represent a refined and targeted approach for the treatment of both conditions through the induction of disease-corrective foetal hemoglobin in human red blood cell progenitors.
  10. Amgen presented data from several studies[5]. These included data evaluating long-term use of Nplate (romiplostim) in paediatric chronic immune thrombocytopenia (ITP).
  11. NoxxonPharmapresented Phase 1 results for its anti-hepcidin NOX-H94 to treat anaemia associated with chronic disease. Excessive concentrations of the peptide hepcidin occur in chronic diseases such as cancer, renal disease, and inflammatory diseases. These concentrations lead to iron restriction, or functional iron deficiency where iron is trapped in its cellular stores and is unavailable for haemoglobin synthesis. NOX-H94 binds to and inactivates hepcidin. The Phase I program consisted of a comprehensive single and multiple ascending dose study in healthy volunteers and a subsequent human pharmacodynamic study to assess the ability of NOX-H94 to prevent endotoxin-induced hypoferraemia in healthy subjects. This study delivered the first clinical evidence that NOX-H94 is capable of neutralizing high levels of hepcidin in humans and maintaining higher serum iron concentrations compared with subjects receiving placebo. NoxxonPharma has begun a Phase IIa clinical trial in Europe in anaemic patients with cancer.

b)Arsenal Medical won a $US15.5 million contract from the US Defense Advanced Research Projects Agency (DARPA)to develop a foam for battlefield use to stem internal bleeding for at least an hour while a patient is transferred to a field hospital. This is to support late-stage development as well as funding work to achieve FDA approval. Arsenal’s long-term goal is to develop the product for civilian use for severe trauma. Pre-clinical data was presented at the 2012 annual meeting of the American Association for the Surgery of Trauma in Kauai. The data demonstrated the foam can treat severe haemorrhage for up to three hours in a lethal model of liver injury. The product could reduce blood loss six-fold and increase survival three hours later from 8 percent to 72 percent.

c)Bayer's BAY 86-6150, a recombinant factor VIIa, is the subject of a Phase II/III study called TRUST (TReatment with Unique recombinant rFVIIa STudy). This will evaluate the safety and efficacy of the compound in patients with haemophilia A or haemophilia B who have developed inhibitors (neutralizing antibodies to clotting factor therapies). Part A of the trial involves sequential dose escalation and assessment of dose response and the pharmacokinetics and pharmacodynamics evaluation. Part B is to confirm efficacy and safety.

d)Kamada announced positive results of the Phase I/II clinical trial of its Alpha-1 Antitrypsin (AAT) protein, the active ingredient in its drug, Glassia, for the treatment of type 1- juvenile onset- diabetes. Analysis of the results found that the AAT protein may halt the progression of diabetes. It enables the pancreas beta cells to continue excreting insulin, providing better glucose balance, thereby lowering or even preventing serious future complications of the disease. In view of the success of the trial and its results, Kamada is preparing further development of injectable AAT for the treatment and curing of juvenile onset diabetes, and to move for regulatory approval. Most patients in the trial reported reduced use of insulin, and there was a corresponding reduction in the level of specific diabetes antibodies, which may indicate a reduction in the autoimmune response in the pancreas.

e)Novo Nordiskin November introduced HemaGo, a mobile application for people with haemophilia and their carers to monitor medications and dosing, details of their bleeds, their pain, and the impact of haemophilia on the rest of their lives.

b)FibroGen and AstellasPharmain December announced the commencement of a Phase III trial of FG-4592/ASP1517 for treatment of anaemia in chronic kidney disease (CKD) patients. The inhibitor of hypoxia-inducible factor prolyl hydroxylase demonstrated the potential to maintain haemoglobin levels, without any intravenous iron supplementation, in CKD patients who are not on dialysis, and in end-stage renal disease patients on dialysis.

f)HalozymeBiotherapeutics works with human enzymes to modify biotechnology medicines for administration by injection rather than intravenously. Its recent agreement with Pfizer includes a licence to develop two specific treatments, and the right for Pfizer to select up to four other targets.

g)CSL, which markets Beriplex, a four-factor prothrombin complex concentrate (PCC), sponsored a study which found Beriplex superior to plasma for urgent reversal of warfarin and other vitamin K antagonists in patients experiencing major bleeding. Dr. Joshua N. Goldstein of the University of Rochester, NY, told the annual meeting of the American College of Emergency PhysiciansthatBeriplex had a higher rate of INR[6] reversal than did plasma at 30 minutes after the start of infusion, based on the Phase IIIb prospective, multicentre, randomized clinical trial. Beriplexwas also shown to be superior to plasma at early replacement of depleted coagulation factors and was noninferior to plasma in terms of blinded investigator–rated haemostatic efficacy in the first 24 hours[7].

Regulatory Matters

The NBA monitors overseas regulatory decisions on products, processes or procedures which are or may be of relevance to its responsibilities.

a)In a Safety Communication on 13 November 2012 the FDA updated information on the risks of thrombosis and haemolysis potentially related to administration of intravenous, subcutaneous and intramuscular human immune globulin products. This follows the FDA Interim Statement Regarding Immune Globulin Intravenous (IGIV), of August 22, 2002, regarding thrombotic events following infusion. The FDA says it continues to investigate whether or not specific characteristics of immune globulin products such as excipients, concentration, or trace procoagulant activity account for an increased risk of thrombosis.

b)Biotest received FDA approval for its polyspecific intravenous immunoglobulin Bivigam for the treatment of patients with primary humoral immunodeficiency. The approval was based on a Phase III study in 63 patients. Participants received 300–800mg/kg of IVIg every three or four weeks for a year. The primary efficacy endpoint was demonstration that the rate of acute serious bacterial infections was <1.0 per person-year. The study achieved its primary endpoints for safety, efficacy, and tolerability. Bivigam will be available in a 10% liquid in 50mL and 100mL vials.

c)The FDA approved Cangene’sVarizig for reducing the severity of chicken pox in high risk individuals when given within four days of exposure. Varizig is a varicella zoster immune globulin preparation.

d)The FDA approved GlaxoSmithKline’s Promacta (electrombopag) for the treatment of thrombocytopenia (low blood platelet counts) in patients with chronic hepatitis C to permit them to initiate and maintain interferon-based therapy.

e)Novartis received approval from the European Commission for Exjade, its oral drug used to reduce iron overload in patients undergoing chelation therapy for non-transfusion-dependent thalassemia, or NTDT, syndrome. The pivotal study, THALASSA, showed a significant dose-dependent decrease in concentration of iron-burden in the body as well as liver in patients on Exjade, compared with placebo. The overall adverse event rate for Exjade was similar to the placebo arm.

f)Medgenics, the developer of the Biopump, which sustains production and delivery of therapeutic proteins using a patient's own tissue, announced a patent from the US Patent and Trademark Office for the use of Medgenics’ EPODURE technology for delivery of erythropoietin (EPO). The USPTO also recognisedclaims for a similar method for delivery of FVIII, underpinning Medgenics’ HEMODUREBiopump technology for sustained prophylaxis in haemophilia. Claims covering EPODURE and HEMODURE were recently recognised in Australia, Japan, China, and Korea.

g)The European Medicines Agency (EMA) held its promised workshop on access to clinical-trial data and transparency. Participants included representatives of the European Federation of Pharmaceutical Industries and Associations, and the Cochrane Collaboration, which has campaigned for Roche to publish the complete raw dataset on its antiviral Tamiflu (oseltamivir). The EMA said it "is committed to proactive publication of clinical-trial data, once the marketing-authorisation process has ended. We are not here to decide if we publish clinical-trial data, but how". The EMA wants r "to build trust and confidence in the system by allowing re-analysis of clinical-trial data by stakeholders". The commitment topublication will apply only to drugs that receive marketing authorisation process from a set date, probably 1 January 2014.

h)In December the European Parliament voted in favour of introducing a unified patent system in 2014. If ratified, the new system is expected to reduce application costs and make Europe more competitive.

i)Ethicon Biosurgery received FDA approval for its EVARREST fibrin sealant patch. This is an adjunct to haemostasis for soft tissue bleeding during open retroperitoneal, intra-abdominal, pelvic and non-cardiac thoracic surgery, when control of bleeding by standard surgical methods (e.g., suture, ligature, or cauterization) is ineffective or impractical. EVARREST is placed upon the bleeding wound surface and manually compressed for three minutes. The human thrombin and fibrinogen initiate a fibrin clot, which integrates into the patch. EVARREST remains in the patient's body supporting the wound site as it is bio-absorbable. The patch is not for use in babies under one month of age, and is not for use in place of sutures or other forms of mechanical ligation in the treatment of major arterial or venous bleeding.

j)Amag has submitted a supplemental new drug application to the FDA for its intravenous Feraheme. The company has asked the FDA to extend the indication for the drug to all iron-deficiency anaemia patients who have failed on, or could not tolerate, oral anaemia drugs, not just to iron-deficiency anaemia patients with CKD. The application is based on data from two Phase III trials (1,400 patients).

k)Anti- coagulant Eliquis has been approved for use in the 27 European Union (EU) countries in patients who have an irregular heartbeat (atrial fibrillation) and are at risk for strokes or systemic embolisms. Eliquis, developed by Bristol-Myers Squibb and Pfizer, had already been approved in the EU in May 2011 for preventing dangerous clots from forming in deep veins after hip or knee replacement surgery. The FDA in December approved Eliquis after earlier rejections and requests for more trial data. The FDA approved the oral treatment for atrial fibrillation, in patients at risk for strokes or dangerous clots, but warned that patients with artificial heart valves should not take the drug as it had not been studied in that population.

l)BoehringerIngelheim’s anti- coagulant Pradaxa (dabigatran) continues to attract discussion.

  1. In November 2012, the FDA issued a Drug Safety Communication informing the public that the Agency has evaluated new information about the risk of serious bleeding associated with use of the anticoagulants Pradaxa and warfarin. Following the approval of Pradaxa, the FDA had received a large number of post-marketing reports of bleeding among Pradaxa users. As a result, the FDA had investigated the actual rates of gastrointestinal bleeding and intracranial hemorrhage for new users of Pradaxa compared with new users of warfarin. The indications were that bleeding rates associated with new use of Pradaxa did not appear to be higher than bleeding rates associated with new use of warfarin, consistent with observations from the RE-LY trial used to approve Pradaxa. The FDA is continuing to evaluate multiple sources of data in the ongoing safety review of this issue.
  2. In December BoehringerIngelheimsaid it would inform physicians that Pradaxa is contraindicated in patients with mechanical heart valves. This followed advice from regulators.
  3. Australia's Pharmaceutical Benefits Advisory Committee (PBAC) advised the government that, because of new information about Pradaxa,"it is of a mind to rescind its March 2011 recommendation" that the drug be available on the Pharmaceutical Benefits Scheme (PBS). A report on the use of anticoagulant therapy was prepared for the government by Emeritus Professor Lloyd Samson. The report says more work is needed before new oral anticoagulants (NOACs) such as Pradaxa can be listed on the PBS. He found actual use of Pradaxa had not matched the clinical trial evidence presented to the PBAC in March 2011, including the average age of patients, the dosage, and the treatment they would otherwise be receiving. In light of this clinical information, the review concluded that the net benefit of NOACs in clinical practice and the subsequent impact on cost-effectiveness "is uncertain." BoehringerIngelheim and the sponsors of other NOACs will be able to make submissions to the March meeting.

m)Cerus Corporation said the FDA had accepted its proposed modular pre market approval application for the INTERCEPT Blood System for plasma. A PMA shell outlines the structure, content and timing of each module, and will allow Cerus to leverage its existing regulatory dossier from European approvals. It will begin the INTERCEPT plasma submission early in 2013. Carol Moore, Cerus' Vice President, Regulatory Affairs, Quality and Clinical, said: "FDA's agreement with our proposal means that we can target completing all four modules in 2013, putting us in a position to receive US approval as early as 2014.”